Effects of Dispersion in Density Functional Based Quantum Mechanical/Molecular Mechanical Calculations on Cytochrome P450 Catalyzed Reactions

Richard Lonsdale, Jeremy N. Harvey*, Adrian J. Mulholland

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

60 Citations (Scopus)

Abstract

Density functional theory (DFT) based quantum mechanical/molecular mechanical (QM/MM) calculations have provided valuable insight into the reactivity of the cytochrome P450 family of enzymes (P450s). A failure of commonly used DFT-methods, such as B3LYP, is the neglect of dispersion interactions An empirical dispersion correction has been shown to improve the accuracy of gas phase DFT calculations of P450s. The current work examines the effect of the dispersion correction in QM/MM calculations on P450s. The hydrogen abstraction from camphor, and hydrogen abstraction and C-O addition of cydohexene and propene by P450(cam), have been modeled, along with the addition of benzene to Compound I in CYP2C9, at the B3LYP-D2/CHARMM27 level of theory. Single point energy calculations were also performed at the B3LYP-D3//B3LYP-D2/CHARMM27 level. The dispersion corrections lower activation energy barriers significantly (by similar to 5 kcal/mol), as seen for gas phase calculations, but has a small effect on optimized geometries These effects are likely to be important in modeling reactions catalyzed by other enzymes also Given the low computational cost of including such dispersion corrections, we recommend doing so in all B3LYP based QM/MM calculations.

Original languageEnglish
Pages (from-to)4637-4645
Number of pages9
JournalJournal of Chemical Theory and Computation
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • ELECTRONIC-STRUCTURE
  • AROMATIC HYDROXYLATION
  • LENNARD-JONES PARAMETERS
  • REBOUND MECHANISM
  • COMPOUND-I
  • P450(CAM) CATALYSIS
  • HYDROGEN ABSTRACTION
  • GAUSSIAN-BASIS SETS
  • MOLECULAR-ORBITAL METHODS
  • EFFECTIVE CORE POTENTIALS

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